A substantial amount of experimental and clinical evidence has supported the role of natural killer (NK) cells in the surveillance and control of malignant transformation. Among the population, there is a range of NK cell activity, and low NK cell activity has been associated with an increased cancer incidence. While heterogeneity in NK cell potency is likely to result, in part, from genetic factors, there is increasing evidence that dietary and environmental factors influence NK cell tumoricidal activity significantly. We have identified a novel role for the aryl hydrocarbon receptor (AhR) in the modulation of NK cell effector functions and anti-tumor activity. This receptor binds a vast number of dietary and environmental ligands, and upon activation, it translocates to the nucleus and regulates transcription of numerous genes. We have observed that agonistic AhR ligands are able to enhance the production of interferon-? and enhance NK cell-dependent tumor rejection of RMA-S lymphomas. Furthermore, animals deficient of AhR have a defect in tumor surveillance, indicating that AhR may play a role in NK cell development and maturation. In this study, we propose experiments to (1) understand the influence of AhR on NK cell anti-tumor effector function and tumor rejection, (2) determine the defect in NK cell anti-tumor activity in AhR-deficient mice, and (3) identify AhR ligands that enhance NK cell effector functions. This work will provide insight into the dietary influences on NK cell-mediated immunosurveillance of tumors and into potential novel anti-cancer therapeutic strategies. PUBLIC HEALTH RELEVANCE: A substantial amount of experimental and clinical evidence has supported the role of natural killer (NK) cells in the surveillance and control of malignant transformation. It is becoming increasingly clear that dietary components are able to influence NK cell activity and cancer susceptibility. However, no good mechanistic explanation has been revealed. The studies that are proposed here will elucidate a novel mechanism by which dietary compounds may influence NK cell anti-tumor activity. This will provide important insight into novel anti-cancer therapeutic strategies.